Abstract Atrial fibrillation (AF) represents one of the most common arrhythmias clinically and is associated with a significant increase in morbidity and mortality, yet, current treatment paradigms remain inadequate. Treatment with conventional antiarrhythmic drugs generally carries a high risk of proarrhythmia. Moreover, prevalence of AF is increasing due to the aging population. We were the first to demonstrate beneficial effects of a novel class of anti-inflammatory agent, soluble epoxide hydrolase (sEH) inhibitors, in clinically relevant models of cardiac hypertrophy and failure. Treatment with sEH inhibitors (sEHIs) results in the prevention of ventricular myocyte hypertrophy and electrical remodeling in pressure overload and MI models. During the last funding cycle, we demonstrate that treatment with sEHIs prevents cardiac fibroblast (CF) proliferation, fibrosis, adverse cardiac remodeling, and AF. These results demonstrate broader salutary effects in cardiac remodeling (not limited to myocyte hypertrophy alone) of this novel class of compounds. The goal of the competing renewal is to test the hypothesis that an increase in the level of endogenous EETs by sEHIs represents a completely unexplored avenue to modify atrial fibrosis by reducing CF proliferation and activation. The proposal represents a bench-to-bedside multidisciplinary study to determine the mechanism and efficacy of using sEHIs for the treatment of AF.